【Nature】地中海贫血症基因疗法试验初获成功
《自然》：地中海贫血症基因疗法试验初获成功
2010/09/25 00:52:28
地中海贫血症患者往往要靠定期输血来保持健康，而一个国际科研小组日前报告说，其开展的以基因疗法治疗一名地中海贫血症患者的试验取得初步成功。这名患者已不再需要输血，并拥有一份正常的工作。
法国、美国、意大利等国科研人员在新一期英国《自然》杂志上报告说，这名男性患者从3年前开始接受基因疗法。当时他18岁，患有β型地中海贫血症。这种病由基因缺陷引起，患者自身不能生成正常的红细胞，因此需要通过输血来保持血液的供养等功能。这名患者从3岁开始输血，严重时每个月都要输血。
在基因疗法试验中，研究人员先利用患者自身的骨髓造血干细胞培养出包括红细胞在内的血液细胞，然后使用病毒作载体，将无缺陷的基因引入这些细胞中，再用化学手段去除多余细胞，只留下基因缺陷得到修正的红细胞，最后将这些红细胞移植回患者体内。
结果显示，患者自身生成正常红细胞的能力逐渐上升，在接受治疗一年后就不再需要输血了。现在该患者虽然仍有轻微贫血症状，但迄今一直不需要输血，并且已经有了一份全职的厨师工作，这说明基因疗法取得了初步成功。
不过也有专家对这一结果持谨慎态度，比如认为试验成功与这名患者自身的一些生理特点有关，可能难以在其他患者身上复制成功经验。试验中使用的病毒带来了一定的副作用，有引发癌症的可能。但是总的来说，这次试验打开了使用基因疗法治疗地中海贫血症的大门，为许多患者带来了希望。
据研究者介绍，β型地中海贫血症多见于地中海地区和东南亚。现有治疗手段除了定期输血外，还有移植造血干细胞等，但通常很难找到匹配的干细胞捐献者，因此基因疗法成为一个新的研究方向。
Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
Marina Cavazzana-Calvo, Emmanuel Payen, Olivier Negre, Gary Wang, Kathleen Hehir, Floriane Fusil, Julian Down, Maria Denaro, Troy Brady, Karen Westerman, Resy Cavallesco, Beatrix Gillet-Legrand, Laure Caccavelli, Riccardo Sgarra, Leila Maouche-Chrétien, Françoise Bernaudin, Robert Girot, Ronald Dorazio, Geert-Jan Mulder, Axel Polack, Arthur Bank, Jean Soulier, Jérôme Larghero, Nabil Kabbara, Bruno Dalle, Bernard Gourmel, Gérard Socie, Stany Chrétien, Nathalie Cartier, Patrick Aubourg, Alain Fischer, Kenneth Cornetta, Frédéric Galacteros, Yves Beuzard, Eliane Gluckman, Frederick Bushman, Salima Hacein-Bey-Abina & Philippe Leboulch
Nature Volume:467, Pages: 318–322. doi:10.1038/nature09328
The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas. The βE-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.